The usefulness of many pharmaceutical and agricultural chemicals and other biologically active agents, such as insect pheromones, depends critically on the fact that the molecules have a chiral atom of one specific chirality. However, usual commercial synthesis of these compounds produces a racemic mixture of the product compound, with half the product of the desired chirality, and half of the opposite chirality. That is, when achiral molecules are resolved, two enantiomers are separated per chiral atom, each of opposite chirality. In commercial synthesis processes that utilize chiral allyl alcohols, the molecules whose chirality is opposite to that desired may be of no use, and in some cases can be detrimental.
In a procedure described in Katsuki et al. U.S. Pat. Nos. 4,471,130 and 4,594,439, secondary allyl alcohols are converted from a racemic mixture to a single enantiomer of the desired chirality. This process is called Sharpless Kinetic Resolution (SKR). The enantiomer of the opposite chirality is converted to an epoxy alcohol whose carbinol carbon atom has the opposite configuration. This produces a substantially pure yield of the desired enantiomer of the allyl alcohol, which amounts to about 50% of the racemic mixture. The other enantiomer, converted to an epoxy alcohol, may be of little value in the synthesis of a specific pheromone or other biological agent.
A procedure for converting the chiral epoxy alcohol that results from the SKR process is discussed in copending U.S. patent application Ser. No. 405,684, filed Sept. 11, 1989, now U.S. Pat. No. 4,935,451. This is a two stage process. The racemic allyl alcohols are kinetically resolved by means of the Sharpless Katsuki process in the presence of a titanium alkoxide or equivalent catalyst. This selectively epoxidizes the enantiomer of the undesired chirality and leaves the allyl alcohol of the desired chirality substantially unreacted. The epoxy alcohol and the allyl alcohol can be physically separated.
The undesired epoxide that results from this reaction is converted back to the allyl alcohol, but with its chiral center inverted to the desired chirality. The epoxy alcohol is converted to an epoxy mesylate or tosylate by action of a methanesulfonic anhydride or a toluenesulfonic anhydride in methylene chloride or other suitable carrier, in which pyridine is present. The resulting epoxy mesylate or tosylate is then converted to the allyl alcohol of the desired chirality by contacting it with tellurium ions, e.g. in the form of an aqueous solution of sodium telluride. By action of the tellurium ions the chiral center is inverted, so that the product allyl alcohol has the same chirality as the alcohol produced by kinetic resolution as practiced above. The efficiency of the synthesis of the desired enantiomer is improved by substantially 100% over the Sharpless Kinetic Resolution alone.
The above technique employing tellurium attack of optically pure secondary glycidyl mesylates is limited to those having a terminal epoxide. The glycidyl mesylates that possess internal epoxides i.e., that are vicinally disubstituted react sluggishly or not at all to this treatment by telluride ion. Therefore, the technique described above was more or less limited to one class of epoxides.
Another problem in this field is that it has been difficult to produce optically active olefins or tertiary allylic or optically active cis-allylic alcohols that have a desired relative diastereomer configuration, i.e., by the SKR technique. Stereospecific cis- or trans- olefins are also useful in producing biologically active agents.